JP2010508995A - Puncture plug containing water-insoluble polymer matrix - Google Patents

Abstract

A pharmaceutical composition comprising a water-insoluble polymer matrix comprising a bioerodible polyester polymer or a fatty acid-based polyester polymer, or a mixture of both polymers, wherein the polymer matrix has a melting point of less than 60 ° C and the composition is liquid at room temperature or Disclosed is a pharmaceutical composition formulated with a paste to occlude a subject's punctal channel and conforms to the shape of a tubule or punctal channel. The present invention overcomes the deficiencies in the art by providing a biocompatible water-insoluble matrix that can be formulated into an injectable composition that can be used to plug a channel of interest.

Description

  The present invention relates generally to the field of implantable ophthalmic compositions. More specifically, it relates to liquid implantable compositions that can be used to treat eye diseases or conditions. In a preferred embodiment, the ocular disease or condition being treated is dry keratoconjunctivitis (ie, dry eye or dry eye syndrome).

  The tear film is a composite structure that serves to protect the surface of the eye. The tear film includes three basic layers: an outer lipid layer, an inner mucin layer, and an aqueous layer between the lipid layer and the mucin layer. Each layer has a specific function. The lipid layer prevents tear evaporation from the surface of the eye. The aqueous layer provides oxygen to the cornea and contains additional chemical components that are important for a healthy eye. The mucin layer provides the interaction between the lipid and aqueous layers and prevents tears from “sphering” on the cornea.

  Approximately 7.5 million cases of moderate or severe dry eye syndrome occur in the United States each year. In addition, 5 million people cannot wear contact lenses due to lack of tears. “Dry eye” is the inadequate lubrication of the cornea that results in the failure of the normal tear film. This condition has a wide variety of signs and symptoms, ranging from mild intermittent burning and / or squeezing with a foreign body sensation to severe aquatic insufficiency with corneal and conjunctival disease (dry keratoconjunctivitis (KCS)). Including.

Dry eye can have a variety of specific causes and contributing factors, including dry environment, environmental air pollutants, certain systemic drugs, autoimmune diseases, drug toxicity, hormone deficiency or change, and even contact lens wear is there. However, the majority of cases of dry eye syndrome are associated with two basic causes. First, when the lacrimal duct from the lacrimal gland is clogged or malfunctions, a sufficient amount of tears do not reach the eyes. In response to this cause, Alcon ^™ Laboratory, Inc. Artificial tear products such as TEARS NATURAL ^™ and BION ^™ TEARS sold by (Fort Worth, Texas) have been developed. Second, the lacrimal glands and lacrimal ducts can deliver a sufficient amount of tears to the eye, but tears can be rapidly drained from the eye, causing a dry eye condition. In contrast, various methods and devices for sealing the punctum have been developed.

  Initially, the punctum was sealed with sutures or by electric or laser ablation. Such means can produce acceptable results, but cannot be reversed without reconstructive surgery. Sometimes it is difficult to determine if dry eye is occurring because of too much drainage or too little tear production, which can expose the patient to unnecessary trauma. In addition, such means can result in tears constantly occurring and accumulating in the eye, resulting in lacrimation that flows to the patient's face.

  A pre-formed collagen plug for insertion into the punctum or tubule has been developed to provide a reversible sealing means. Collagen plugs are water soluble and typically dissolve within 7 to 14 days when inserted into the punctum. Therefore, the collagen plug is effective as an inspection means for determining whether it is desirable to seal the punctum more permanently.

  Various preformed water insoluble plugs for insertion into the punctum or tubule are described in various US patents. For example, US Pat. No. 3,949,750 to Freeman describes such a plug having a head that extends outside the punctum and a barb that reaches the punctum and / or tubule. Such plugs can be seen in the corners of the eye, are sometimes uncomfortable and easily come off. Furthermore, such plugs are somewhat difficult to insert, and sometimes their size and shape cause tissue damage during insertion. If such plugs protrude far from the punctum, they can cause irritation to the sclera. In addition, the punctal tissue can be damaged due to prolonged dilation caused by such plugs.

  US Pat. No. 5,283,063 to Freeman describes a similar plug made from a hydrogel material having a hydrated port located in the barb, where the tubule liquid is barbed. Allowing the plug to hydrate to an expanded, relatively flexible state. US Pat. Nos. 5,723,005 and 5,171,270 belonging to Herrick describe a water-insoluble punctal plug with a foldable flared portion to improve sealing and fixation within the tubule. is doing. Also, some of these plugs have a holding portion that expands outside the punctum to further secure the plug and prevents movement to the tubule.

  U.S. Pat. No. 5,469,867 to Schmitt discloses lacrimal tubules and other mammalian channels by injecting a heated fluid polymer or polymer composite of a specific composition into the tubule through the punctum. Or describes how to close the tube. Certain polymers and polymer conjugates are non-immunogenic biocompatible materials that are solid and / or non-flowable at body temperature and are flowable when heated slightly above body temperature. Polymers and polymer composites can be rapidly changed from a fluid state to a non-flowable state by changing the temperature by only a few degrees. After injection, the polymer or polymer composite cools and solidifies to form a plug that exactly matches the dimensions of the tubule. However, heated polymers and heated delivery devices can cause burns that can damage delicate tissue structures during insertion. Another concern is the melting temperature of the polymer. If the melting temperature is higher than the subject's body temperature, there is a significant risk of burns to delicate tissues. Furthermore, if the melting temperature is below 45 ° C., undesired softening can occur, such as when the subject is hot or sits in front of a fireplace. This results in the loss of this material from the lacrimal system.

  The present invention overcomes the deficiencies in the art by providing a biocompatible water-insoluble matrix that can be formulated into an injectable composition that can be used to plug a channel of interest.

  More specifically, the present invention generally relates to a pharmaceutical composition comprising a water-insoluble polymer matrix comprising a polyester polymer or a fatty acid-based polymer, or a mixture of both polymers, wherein the polymer matrix has a melting point of less than 60 ° C. And relates to a pharmaceutical composition that is formulated so as to occlude a channel of interest in a liquid or paste at room temperature.

  The term “subject” refers to any human or non-human such as primates, mammals and vertebrates. In certain embodiments, the subject is a human.

  As used herein, “channel” is defined to refer to a tubular flow path in a subject. In certain embodiments, the channel is a tubule channel or a punctal channel.

  “Clogging” or “occlusion” as used in the context of the present invention refers to blocking or blocking a flow path through a channel associated with the flow path in the absence of the composition of the present invention. Thus, “blocking” as used herein refers to total and partial blockage of the channel.

  The period of occlusion can be permanent or temporary. The occlusion can continue for any period of time. For example, in certain embodiments, the composition is formulated to block the channel for at least one year. In other embodiments, the composition is formulated to occlude the channel for less than one year.

  The composition may include any additional ingredients known to those skilled in the art. For example, in some embodiments, the composition comprises up to 20% water miscible organic liquid. The water miscible organic solvent may or may not be miscible with the polymer matrix. In certain embodiments, the water miscible organic liquid is miscible within the polymer matrix.

  The polyester polymer can be any polyester polymer known to those skilled in the art. For example, the polymer matrix can be poly (caprolactone), poly (ethylene glycol adipate), poly (propylene glycol adipate), poly (butylene glycol adipate), poly (hydroxybutarate), poly (hydroxyvalerate) and its Polyester polymers selected from the group consisting of mixtures and copolymers may be included. In certain embodiments, the polymer matrix comprises a poly (caprolactone) polymer. For example, the polymer matrix can include a polyester polymer selected from the group consisting of:

（式中、Ｒ_１、Ｒ_２およびＲ_３は、独立に２から８個の炭素原子のアルキルならびにアルコキシルジオール、トリオールおよびテトラオールから成る群から選択され、
ｗ、ｗ_１は、独立に４から１２の整数であり、
ｗ_２、ｗ_３は、独立に１から１２の整数であり、
ｗ_４、ｗ_５、ｗ_６、ｗ_７、ｗ_８、ｗ_９およびｗ_１０は、独立に０から１２の整数であり、
ｎは、４から９の整数であり、
ｍは、２から８の整数である）。

Wherein R ₁ , R ₂ and R ₃ are independently selected from the group consisting of alkyl of 2 to 8 carbon atoms and alkoxyldiol, triol and tetraol;
w and w ₁ are independently integers of 4 to 12,
w ₂ and w ₃ are each independently an integer of 1 to 12,
w ₄ , w ₅ , w ₆ , w ₇ , w ₈ , w ₉ and w ₁₀ are independently integers from 0 to 12,
n is an integer from 4 to 9,
m is an integer from 2 to 8).

Non-limiting examples of R ₁ , R ₂ and R ₃ alkyls and alkoxyl diols, triols and tetraols include butanediol, hexanediol, neopentyl glycol, diethylene glycol, trimethylolpropane and pentaerythritol. An example of a polyester polyol in which R ₁ is butanediol is as follows:

本発明の医薬組成物の脂肪酸系ポリマーは、当業者に公知の任意の脂肪酸系ポリマーであり得る。例えば、ポリマーマトリックスは、次式の構造を有する脂肪酸系ポリマーを含み得る

The fatty acid polymer of the pharmaceutical composition of the present invention can be any fatty acid polymer known to those skilled in the art. For example, the polymer matrix can include a fatty acid-based polymer having the structure:

（式中、Ａは、６から６０個の炭素原子の脂肪族ヒドロキシカルボン酸エステルであり、
Ｂは、８から４０個の炭素原子の不飽和脂肪酸の二酸ダイマーであり、
ｎは、０から３の整数である）。

In which A is an aliphatic hydroxycarboxylic acid ester of 6 to 60 carbon atoms;
B is a diacid dimer of an unsaturated fatty acid of 8 to 40 carbon atoms;
n is an integer from 0 to 3).

  As used herein, “aliphatic hydroxycarboxylic acid ester” is defined to refer to a linear, branched and / or cyclic aliphatic hydrocarbon chain containing one or more hydroxy groups and one or more ester groups. Is done. For example, in some embodiments, A has the structure:

（式中、ａ、ｂ、ｃ、ｄ、ｅおよびｆは、独立に１〜１５個以上の直鎖状炭素の範囲のアルキル基である）。

(Wherein a, b, c, d, e and f are independently alkyl groups in the range of 1-15 or more linear carbons).

  As used herein, a “diacid dimer” is a 5-8 carbon cyclic aliphatic and / or aromatic containing at least two carboxylic acid substituents covalently bonded to at least two aliphatic hydroxycarboxylic acid esters. Is defined to refer to a dimer comprising a group hydrocarbon core structure. The core structure may include additional substituents such as H and / or alkyl groups of 1 to 15 carbons. In some embodiments, B has the structure:

（式中、ｇ、ｈ、ｉおよびｊは、独立に１〜１５個以上の直鎖状炭素の範囲のアルキル基である）。

(Wherein g, h, i and j are independently alkyl groups in the range of 1 to 15 or more linear carbons).

  The polymer matrix can contain polymers of any molecular weight. In some embodiments, the polymer matrix contains a polymer having an average molecular weight of 400 to 8,000. Furthermore, the polymer matrix may have any viscosity. In certain embodiments, the viscosity of the polymer matrix is 50 to 8,000 cps at 55 ° C.

  The polymer matrix may be bioerodible or non-bioerodible. In certain embodiments, the polymer matrix or composition is bioerodible.

  In certain embodiments, one or more active agents are dispersed within the polymer matrix. An active agent includes, but is not limited to, any component, compound or small molecule that can be used to produce a desired effect. For example, the desired effect can include diagnosis, cure, alleviation, treatment or prevention of a disease or condition. In certain embodiments, the active agent is a drug.

  In some embodiments, the composition is formulated to provide controlled release of the active agent over a predetermined period of time. Controlled release formulations are well known to those skilled in the art and are described elsewhere herein.

  The active agent can be any active agent known to those skilled in the art. In certain embodiments, the active agent is an eye drop. The active agent may or may not be in solution or suspension.

  The composition can be formulated in any manner known to those of skill in the art. In some embodiments, the composition is formulated into an injectable paste or liquid.

  In some embodiments, the composition is contained in a syringe or other device suitable for infusion of the composition into the channel.

  The present invention also generally relates to a method of occluding a subject channel related to administering one of the pharmaceutical compositions of the invention to the subject channel. The composition may or may not require preheating prior to administration. In certain embodiments, the pharmaceutical composition is not preheated prior to administering the composition to the channel. As described above, the channel can be any channel. One example of a channel is a tubule channel. Another example is the punctal channel.

  The channel can be formulated to plug the channel for any period of time. In certain embodiments, the channel is blocked for at least one year. In other embodiments, the channel is blocked for a short period of time, such as a week or a month.

  Any method of administering a composition known to those skilled in the art is contemplated by the present invention. For example, in some embodiments, the pharmaceutical composition is injected into the channel with a needle.

  The pharmaceutical composition can be of any viscosity. In some embodiments, the pharmaceutical composition is non-flowable. In other embodiments, the pharmaceutical composition conforms to the shape of the channel.

  The present invention also generally administers a pharmaceutical composition of the present invention to a tubule or punctal channel of a subject, and the composition drains tear fluid from the eye through the tubule channel or punctal opening of the subject. It relates to a method of treating dry eye syndrome in a subject related to reducing blood pressure. In some embodiments, the pharmaceutical composition is not preheated prior to administering the composition to the tubule or punctal channel.

  A pharmaceutical composition administered to a subject may or may not be fluid. In some embodiments, the pharmaceutical composition is formed into the shape of a tubule or punctal channel. In other embodiments, the pharmaceutical composition is formulated into an injectable paste or liquid.

  The present invention also relates to a kit comprising the pharmaceutical composition of the present invention and a device for administering the pharmaceutical composition to a subject. The kit is described in further detail in the following specification. The device for administering the pharmaceutical composition can be any device known to those skilled in the art. For example, the device can include a syringe. It may also include a needle.

  It is contemplated that any embodiment described herein can be implemented with respect to any method or composition of the invention (and vice versa). Furthermore, the compositions of the present invention can be used to accomplish the methods of the present invention.

  “Room temperature” includes the ambient temperature of a given room (eg, laboratory, medicine cabinet, bathroom, etc.), and in the most standard case this may include a temperature of about 15 ° C. to about 25 ° C.

  The phrases “blocking channel” or “blocking channel” or any variation of these phrases, as used in the claims and / or specification, refer to the transport or movement of another substance through the channel. A process that partially and / or completely fills at least part or part of a channel, flow path, opening, cavity or space with an obstructing and / or completely preventing substance. This “another substance” can be of biological origin such as sperm, ovum, tears or blood, or it can be a prosthesis such as a metal rod or pin. In a preferred embodiment, the channel is completely blocked and prevented from all flow.

  The term “bioerodible” refers to a composition of the invention due to the action of a bioenvironmental cue (eg, target site acidity, temperature or moisture, presence of an enzyme, protein or other molecule at the target site). Product and / or polymer degradation, depolymerization or digestion.

  The term “matrix” relates to the physical structure of the polymer of the present invention. In some embodiments, the active agent can be mixed with the polymer matrix.

  The term “subject” refers to either a human or non-human such as primates, mammals and vertebrates. In certain embodiments, the subject is a human.

  The term “about” or “approximately” is defined as approximate, as will be understood by those skilled in the art, and in one non-limiting embodiment, the term is within 10%, preferably within 5%, more Preferably defined as within 1% and most preferably within 0.5%.

  The terms “inhibiting”, “decreasing” or “preventing”, or any variation of these terms, as used in the claims and / or the specification, are used to achieve the desired result. Including any measurable reduction or complete inhibition.

  The term “effective” means that the term is used in the specification and / or claims to be sufficient to achieve the desired, expected, or intended result.

  The use of the word “a” or “an” when used in connection with the term “comprising” in the claims and / or the specification may mean “one”, but “one or more” Is also consistent with the meanings of “at least one” and “one or more”.

  In the claims, the use of the term “or” clearly indicates that the choice is only, or that the choices are mutually exclusive, even though the disclosure only supports the choice and the definition of “and / or”. Unless used, it is used to mean “and / or”.

  As used in this specification and in the claims, “comprising” (and any form of inclusion, such as “includes”), “having” (and “having”, etc., any Form), “including” (and any form of inclusion, such as “include”), or “containing” (and any form of inclusion, such as “include”) Or non-limiting and does not exclude additional elements or method steps not listed.

  Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and examples illustrate specific embodiments of the invention, but are given by way of illustration only. Further, it is contemplated that changes and modifications within the spirit or scope of the invention will become apparent to those skilled in the art from this detailed description.

The following drawings form part of the present specification and are included to further demonstrate certain non-limiting aspects of the invention. The invention may be better understood with reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.
1 is a schematic cross-sectional view showing a lacrimal duct system of a mammalian eye. 1 is a schematic cross-sectional view of a tubule channel blocked with a composition of the present invention.

  Unless otherwise stated, all component amounts expressed as percentages are in percent weight / weight terms (% by weight).

  As noted above, approximately 7.5 million cases of moderate or severe dry eye syndrome occur in the United States each year. The condition ranges from mild intermittent burning and / or squeezing with a foreign body sensation to severe aquatic secretion deficits with corneal and conjunctival disease (dry keratoconjunctivitis (KCS)). including. Current treatment options are often ineffective and can be difficult to handle. For example, preformed water-insoluble plugs for insertion into the punctum or tubule are sometimes uncomfortable and easily dislodged. Furthermore, injectable compositions that require preheating may be cumbersome and may require specialized equipment.

  The present invention overcomes these deficiencies in the art by providing a biocompatible water-insoluble matrix that can be formulated into an injectable liquid composition or paste that can be used to plug a channel of interest. The water-insoluble matrix can comprise a bioerodible polyester polymer or a non-bioerodible fatty acid-based polyester polymer, or a mixture thereof. In certain embodiments, the composition can be used to treat dry eye syndrome by administering the composition to the tubule or punctal channel of a mammalian eye.

  These and other non-limiting aspects of the invention are described in further detail in the following sections.

A. Therapeutic applications In general, the compositions of the present invention block any type of channel (eg, block any type of organism and non-living channels and all types of channels outside the biological system and Can even be used to block even tubular devices). Blocking the channel using the compositions of the present invention can prevent or reduce the transfer of substances into or out of the channel within the host.

  Typically, the composition of the present invention is injected or extruded from a container into an infusion device (e.g., holding or containing the composition of the present invention in its chamber and blocking a tube or channel). Any device) can be inserted into the channel. Non-limiting examples of infusion devices that can be used include plastic tip applicators, catheters, reservoirs, plungers, release systems, plastic tubes, microcannulas, taper cannulas and various types commonly known and available to medical professionals Including syringes and hypodermic needles. The amount of polymeric material provided in the infusion device can vary depending on the particular channel being blocked and the amount and type of block desired. It is contemplated that one skilled in the art will understand that the amount of composition contained within the infusion device may depend on the size of the channel being blocked. Further, the size of the tip or nozzle of the infusion device can be related to the inner diameter of the channel being placed. For example, a 24 gauge needle easily fits within the punctum opening leading to the small tube.

1. Dry Eye Syndrome In certain embodiments, the compositions of the present invention can be used to treat dry eye syndrome. FIG. 1 illustrates the lacrimal duct system of a mammalian eye 10. The lacrimal duct system includes a lower punctum 12 connected to the lower tubule 14 and an upper punctum 16 connected to the upper lacrimal duct 18. The tubules 14 and 18 are connected to the lacrimal sac 20 and the nasolacrimal duct 22. The lacrimal gland 24 is connected to the eye 10 through the lacrimal duct 26. In general, tears are produced by the lacrimal gland 24 and supplied to the eye 10 through the lacrimal duct 26. Then, the tears are discharged from the eye 10 through the punctum 12 and the tubule 14, the punctum 16 and the tubule 18, and the nasolacrimal duct 22.

  As noted above, the effects of dry eye syndrome can be treated by occluding the tubules 14, 18 or punctal 12, 16 channels of the mammalian eye 10, thereby allowing the eye to pass through the tubules and punctal channels. Tear drainage can be reduced or prevented. For example, the nozzle of the infusion device can be inserted into the punctum 12, 16 and / or tubule 14, 18 channel through the lower punctum or upper punctum opening. The composition can be injected into the channel from a nozzle. The infusion continues until the desired amount of blockage is obtained. In some cases, it may be desirable to block only a portion of the channel (ie, allow partial flow) or block the entire channel. In certain embodiments, the composition can be injected into the channel to cause the polymeric material to conform to the inner wall of the channel that fills and is blocked. Thereafter, the nozzle of the injection device is withdrawn.

  FIG. 2 illustrates lacrimal tubules 14 and 18 respectively blocked or occluded by the compositions (30 and 32) of the present invention. As shown in FIG. 2, compositions 30 and 32 completely block tubules 14 and 18, but if desired, the composition is simply blocked in a manner that partially blocks tubules 14 and 18. Can be compounded and / or inserted. Furthermore, if desired, compositions 30 and 32 can be formulated to extend to the bulk 19 and 21 or any other portion of the channel shown in FIGS.

2. Non-limiting examples of other channels that can be occluded Non-limiting examples of other channels that can be blocked by the present invention include the fallopian tubes, vas deferens, arteries, blood vessels and bone lumens. Thus, it is contemplated that the compositions of the present invention can be used in other therapeutic applications that perform blockage of specific channels. For example, U.S. Pat. No. 5,469,867 to Schmitt (cited) inserts an injectable composition into the appropriate channel, thereby closing the reproductive channel, closing the blood supply, and Describes a method for correcting vascular abnormalities, closing a temporary created channel for a cranial tap, and securing a pin in a bone lumen. It is also contemplated that the compositions of the invention can be used in a similar manner (ie, injecting the composition into the appropriate channel to partially or completely block the channel).

B. Water Insoluble Polymer Matrix The water insoluble polymer matrix of the present invention can be formulated into an injectable liquid or paste that can be used to plug a channel of interest. In certain embodiments, the polymer matrix has a melting point of less than 60 ° C. The matrix preferably comprises a polymer having an average molecular weight of 400 to 8,000 and / or a viscosity of 50 to 8,000 cps at 55 ° C.

1. Bioerodible Polyester Polymer The matrix of the present invention can comprise a polyester polymer. Non-limiting examples of bioerodible polyester polymers that can be used include poly (ε-caprolactone), poly (alkylene glycol adipate) (eg, poly (ethylene glycol adipate), poly (propylene glycol adipate), poly (Butylene glycol adipate)) and mixtures and copolymers thereof. Poly (caprolactone) polymer is a preferred polyester polymer, under the trade names TONE ^™ Polyol and CAPA ^™ Polyol, respectively, Dow Chemical Company (Midland, Mich.) And Solvay Chemicals, Inc. (Located in Houston, Texas).

  Table 1 below contains non-limiting examples of water-insoluble polyester polymer matrices that can be used in the context of the present invention. These polymers are based on polycaprolactone. The physical properties and commercial availability of these polymers are listed in Table 1.

ＰＣＬ−９００＝Ｔｏｎｅ３１０＝ＣＡＰＡ３０９１＝トリオールとしてＴＭＰ含有ポリカプロラクトントリオール
ＣＡＰＡ２１０１Ａ＝Ｔｏｎｅ２２２１＝ジオールとしてＮＰＧ含有ポリカプロラクトンジオール
ＣＡＰＡ ＰＬ−１０００＝ポリオール含まない１，０００のｍｗでのポリカプロラクトン
Ｔｏｎｅ１２３２＝ジオールとしてブタンジオール（ＢＤＯ）含有ポリカプロラクトンジオール
ＴＭＰ＝トリメチロールプロパン
ＮＰＧ＝ネオパンチルグリコール
ＢＤＯ＝ブタンジオール
ＰＥＮＴＡ＝ペンタエリトリトール。

PCL-900 = Tone 310 = CAPA3091 = TMP-containing polycaprolactone triol as triol CAPA2101A = Tone 2221 = NPG-containing polycaprolactone diol as diol CAPA PL-1000 = Polycaprolactone Tone1232 at 1,000 mw without polyol (butanediol as diol) BDO) -containing polycaprolactone diol TMP = trimethylolpropane NPG = neopandol glycol BDO = butanediol PENTA = pentaerythritol.

  The degradation rate of the polymers in Table 1 was measured by monitoring weight loss after storage in phosphate buffered saline (PBS) at pH 7.4. Weight loss was measured after exposing the polymer to PBS saline at 37 ° C. Saline was removed, vials were dried and weight loss was measured. The degradation rates after 2 weeks and 4 weeks are shown in Table 2 below. The pH of the saline solution (initially pH 7.4) is reported below.

＊３７℃、ｐＨ７．４でＰＢＳ１０ｍｌ中にポリマー１ｇ
＊＊３７℃、ｐＨ７．４でＰＢＳ２０ｍｌ中にポリマー１ｇ
＊＊＊３７℃、ｐＨ７．４でＰＢＳ２０ｍｌ中にポリマー０．５ｇ
ＮＴ＝試験せず。

* 1 g of polymer in 10 ml of PBS at 37 ° C. and pH 7.4
** 1g polymer in 20ml PBS at 37 ° C, pH 7.4
*** 0.5g polymer in 20ml PBS at 37 ° C, pH 7.4
NT = not tested.

  In another non-limiting embodiment, the polyester polymer of the present invention can be selected from the group consisting of:

（式中、Ｒ_１、Ｒ_２およびＲ_３は、独立に２から８個の炭素原子のアルキルならびにアルコキシルジオール、トリオールおよびテトラオールから成る群から選択され、
ｗ、ｗ_１は、独立に４から１２の整数であり、
ｗ_２、ｗ_３は、独立に１から１２の整数であり、
ｗ_４、ｗ_５、ｗ_６、ｗ_７、ｗ_８、ｗ_９およびｗ_１０は、独立に０から１２の整数であり、
ｎは、４から９の整数であり、
ｍは、２から８の整数である）。

Wherein R ₁ , R ₂ and R ₃ are independently selected from the group consisting of alkyl of 2 to 8 carbon atoms and alkoxyldiol, triol and tetraol;
w and w ₁ are independently integers of 4 to 12,
w ₂ and w ₃ are each independently an integer of 1 to 12,
w ₄ , w ₅ , w ₆ , w ₇ , w ₈ , w ₉ and w ₁₀ are independently integers from 0 to 12,
n is an integer from 4 to 9,
m is an integer from 2 to 8).

Non-limiting examples of R ₁ , R ₂ and R ₃ alkyls and alkoxyl diols, triols and tetraols include butanediol, hexanediol, neopentyl glycol, diethylene glycol, trimethylolpropane and pentaerythritol.

  The polyester polymer matrix of the present invention can be prepared by a number of different processes known to those skilled in the art. For example, a polyester polymer matrix can be prepared by heating to reduce viscosity and, for example, by sterile filtering by using a 0.22 μm membrane filter. Furthermore, the polymer matrix can be sterilized by many different processes known to those skilled in the art. For example, the polymer matrix can be sterilized by dry heat, gamma irradiation or other common sterilization methods.

  The polyester polymer matrix of the present invention generally comprises the polyester polymer in an amount of at least 50%, preferably at least 70%, and more preferably at least 80%. In some embodiments, the composition comprises a polyester polymer in an amount of at least 85%. In other embodiments, the composition of the present invention comprises a polyester polymer in an amount of at least 95%. In yet another embodiment, the composition comprises a polyester polymer in an amount of at least 99%.

2. Fatty acid-based polyester polymer The matrix of the present invention may comprise a fatty acid-based polymer. Fatty acid-based polyesters are currently used in a wide variety of products (eg, coatings, adhesives, sealants, elastomers and foams), and have found use in cosmetic and personal care products. . Certain fatty acid-based polymers are dimers, and non-limiting examples of such dimers include, for example, the structure:

（式中、Ａは、６から６０個の炭素原子の脂肪族ヒドロキシカルボン酸エステルであり、Ｂは、８から４０個の炭素原子の不飽和脂肪酸の二酸ダイマーであり、ｎは、０から３の整数である）。ある実施形態において、Ａの脂肪族ヒドロキシカルボン酸エステルは、次式の構造を有する

Wherein A is an aliphatic hydroxycarboxylic acid ester of 6 to 60 carbon atoms, B is a diacid dimer of an unsaturated fatty acid of 8 to 40 carbon atoms, and n is from 0 to 3). In certain embodiments, the aliphatic hydroxycarboxylic acid ester of A has the structure:

（式中、ａ、ｂ、ｃ、ｄ、ｅおよびｆは、互いに独立に１〜１５個以上の直鎖状炭素の範囲のアルキル基である）。ある実施形態において、Ｂの不飽和脂肪酸の二酸ダイマーは、次式の構造を有する

(Wherein a, b, c, d, e and f are each independently an alkyl group in the range of 1 to 15 or more linear carbons). In some embodiments, the unsaturated fatty acid diacid dimer of B has the structure:

（式中、ｇ、ｈ、ｉおよびｊは、互いに独立に１〜１５個以上の直鎖状炭素の範囲のアルキル基である）。ある特定の実施例において、Ａは、次式である。

(Wherein g, h, i and j are each independently an alkyl group having a range of 1 to 15 or more linear carbons). In one particular embodiment, A is

ある特定の実施例において、Ｂは、次式である。

In one particular embodiment, B is:

また、本発明の脂肪酸系ポリマーは、次式の構造によって表すことができる

The fatty acid polymer of the present invention can be represented by the structure of the following formula.

（式中、Ａは、次式であり、

(In the formula, A is the following formula,

Ｂは、次式であり、

B is:

Ｒ_１、Ｒ_２、Ｒ_３、Ｒ_５およびＲ_６は、互いに独立に１〜３０個以上の直鎖状炭素の範囲のアルキル基である）。

R ₁ , R ₂ , R ₃ , R ₅ and R ₆ are each independently an alkyl group in the range of 1 to 30 or more linear carbons).

  Such a fatty acid-based polyester is prepared by an esterification reaction between a diol or a polyol (for example, an aliphatic hydroxycarboxylic acid) and a fatty acid dimer. An example of a fatty acid dimer is hydrogenated castor oil dimer linoleic acid, which is available from Kokiyu Alcohol Kogyo Co. , Ltd (location, Tokyo, Japan) (eg RISCOCAST, 3,900 and 6,800 g / mol molecular weight).

上記のダイマーなどの脂肪酸系ポリマーは、他のポリマー（例えば、ポリエーテルおよびポリウレタン）に勝る多くの利点を有する。例えば、脂肪酸系ポリマーは、緩徐な生分解を受けるのみで、熱、酸化および紫外（ＵＶ）線に比較的安定である。さらに、比較的少ないエステル結合を囲む疎水性環境は、有機化合物との互換性、および他のポリエステルポリオールと比べて比較的高い加水分解安定性をもたらす。また、これらエステルの加水分解安定性は、酸、アルカリおよびアルコールによる抵抗をもたらす。

Fatty acid-based polymers such as the dimers described above have many advantages over other polymers (eg, polyethers and polyurethanes). For example, fatty acid-based polymers only undergo slow biodegradation and are relatively stable to heat, oxidation and ultraviolet (UV) radiation. In addition, the hydrophobic environment surrounding relatively few ester bonds provides compatibility with organic compounds and relatively high hydrolytic stability compared to other polyester polyols. Also, the hydrolytic stability of these esters results in resistance by acids, alkalis and alcohols.

  Other properties of fatty acid polymers are tensile compared to certain polyols and polyethers such as 1,4-butanediol-adipate (BDO-adipate), polypropylene glycol (PPG) and polybutadiene-diol (PB-diol). Includes good maintenance of strength and extensibility, flexibility combined with good impact strength and adhesion to low energy surfaces. For example, fatty acid-based polyester polyol dimers sold by Uniqema (location Gouda, The Netherlands) under the trade name PRIPLAST (molecular weight range of 1,300-3,200 g / mol) exhibit these properties. Also, PRIPLAST polymers can be easily converted to polyurethanes characterized by properties such as good extensibility, tensile strength and Shore A hardness. When used in the context of the present invention, fatty acid-based polymers such as PRIPLAST and / or RISCOCAST may provide favorable properties as described above.

C. Active Agent In certain non-limiting embodiments, the water-insoluble polymer matrix of the present invention can include an active agent. An active agent includes, but is not limited to, any component, compound or small molecule that can be used to provide a desired effect. Non-limiting examples of desired effects of the present invention include therapeutic effects. For example, the desired effect can include diagnosis, cure, alleviation, treatment or prevention of a disease or condition. An active agent can also affect the structure or function of a body part or organ of a subject.

  In certain embodiments, the active agent is a hydrophobic drug. Hydrophobic active agents include agents that are sparingly soluble in aqueous media (eg, not completely dissolved in the media at concentrations administered in aqueous compositions). Thus, depending on use and concentration, the active agent may be considered water insoluble in one situation but not water insoluble in another. However, one skilled in the art will recognize that the active agent need not be a hydrophobic drug within the context of the present invention.

A preferred class of active agents includes eye drops. Non-limiting examples include anti-glaucoma agents, anti-angiogenic agents, anti-infective agents, anti-inflammatory agents, growth factors, immunosuppressive agents and anti-allergic agents. Anti-glaucoma agents include β-blockers (eg, timolol, betaxolol, levobetaxolol and carteolol), miotic agents (eg, pilocarpine), carbonic anhydrase inhibitors (eg, brinzolamide and dorzolamide), prostaglandins. Gin (eg, travoprost, bimatoprost and latanoprost), seretnergic, muscarinic, dopaminergic agonists, and adrenergic agonists (eg, apraclonidine and brimonidine). Anti-angiogenic agents include anecoltab acetate (RETAANE ^™ , Alcon ^™ Laboratories, Inc., Fort Worth, TX) and receptor tyrosine kinase inhibitors. Anti-infective agents include quinolones (eg, ciprofloxacin, moxifloxacin and gatifloxacin) and aminoglycosides (eg, tobramycin and gentamicin). Anti-inflammatory agents include non-steroidal and steroidal anti-inflammatory agents such as suprofen, diclofenac, ketorolac, nepafenac, rimexolone and tetrahydrocortisol. Growth factors include EGF. Antiallergic agents include olopatadine and epinastine. Eye drops may be present in the form of pharmaceutically acceptable salts such as timolol maleate, brimonidine tartrate or sodium diclofenac.

  In one embodiment, the eye drops are known classes of intraocular pressure-lowering drugs such as carbonic anhydrase inhibitors, beta blockers, prostaglandins, bradykinin agonists, rho kinase inhibitors, CNP receptor agonists and guanylate cyclase activators. Selected from the group consisting of

  While eye drops are the preferred active agents of the present invention, the inventors contemplate that other active agents can be used. The following includes non-limiting examples of these other active agents, and it should be recognized that some of these active agents can be generic or identical to the eye drops defined above. This is because some eye drops can be used to treat or prevent other diseases or conditions. In addition, some of the following active agents not defined in the above section may also be used to treat eye diseases or conditions. Active agents such as nucleic acids, proteins and peptides, hormones and steroids, chemotherapeutic agents, NSAIDs, vaccine components, analgesics, antibiotics, antidepressants are contemplated as useful in the context of the present invention.

D. Pharmaceutical Composition In a preferred embodiment, the pharmaceutical composition of the present invention is a liquid at room temperature. In certain embodiments, the active agent is dispersed throughout the matrix. The phrase “pharmaceutically or pharmacologically acceptable” can include molecular entities and compositions that, when administered to a subject such as, for example, a human, do not produce harmful, allergic or other adverse reactions. It is not limited to. The preparation of pharmaceutical compositions is generally known to those skilled in the art. Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990. In addition, for animal (eg, human) administration, the preparation preferably meets sterilization, pyrogenicity, general safety and purity standards as required by the FDA Office of Biological Standards.

  A “therapeutically effective amount” is an amount that is effective to produce beneficial results for the recipient. Such amount can be determined initially by reviewing the published literature, by performing in vitro tests, or by conducting metabolic studies of healthy laboratory animals. Prior to use in a clinical setting, it may be beneficial to conduct a confirmatory study in an animal model, preferably a widely accepted animal model of the particular disease being treated. A preferred animal model used in certain embodiments is a rodent model. This model is preferred because it is economical to use and, in particular, the results obtained are widely accepted as predicting clinical value.

  “Pharmaceutically acceptable carrier” refers to any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (eg, antibacterial and antifungal agents), isotonic agents, absorption delays Agents, salts, preservatives, drugs, drug stabilizers, gels, binders, excipients, disintegrants, lubricants, sweeteners, fragrances, dyes, such substances known to those skilled in the art and combinations thereof (Remington's, 1990).

  The actual dose of the composition of the invention to be administered to a subject is the physical and physiological such as body weight, severity of the condition, type of disease being treated, previous or concomitant therapeutic intervention, patient sudden onset disease and route of administration. It can be determined by factors. The practitioner responsible for administration will, in any event, determine the concentration of the active ingredient in the composition and the appropriate dose for the individual subject.

  The composition containing the bioerodible polymer matrix can further contain up to 20% of a water miscible organic liquid that can be mixed with the polyester polymer described above. In some embodiments, the amount of water miscible organic liquid is 10% or less. Examples of miscible organic liquids are propylene glycol and polyethylene glycol. These liquids are also water soluble, thus altering the in vivo drug release profile and the degradation rate of the polyester polymer matrix. In addition, these organic liquids reduce the viscosity of the drug loaded matrix.

  The composition should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microorganisms such as bacteria and fungi. Of course, exotoxin contamination must be kept to a minimum at a safe level (eg, less than 0.5 ng / mg protein).

  One skilled in the art will appreciate that the compositions of the present invention may also include any number of ingredients (eg, active agents, polymers, excipients, etc.) combinations. It is also contemplated that the concentration of these components can vary. In certain non-limiting embodiments, the pharmaceutical composition can comprise, for example, at least about 0.001% by weight of the active ingredient. In other embodiments, the active ingredient may constitute from about 0.002% to about 50% by weight of the composition, and any range obtained there. In yet other embodiments, the active ingredient may comprise from about 0.5% to about 5% of the composition. In further embodiments, the concentration of active agent is from about 5% to about 30%. In still further embodiments, the concentration of active agent in the device is from about 10% to about 20% by weight. One skilled in the art will appreciate that the concentration may vary depending on the addition, substitution and / or weight loss of the components in a given composition.

E. Component Sources The ingredients and components of the compositions of the present invention as set forth in the claims and specification can be obtained by any method known to those skilled in the art. In a non-limiting embodiment, for example, these components can be isolated by obtaining a source of such compounds, agents and active ingredients. In many cases, the ingredients are commercially available.

F. Modifications and Derivatives Modifications or derivatives of the components disclosed throughout this specification are contemplated as useful in the methods and compositions of the invention. Derivatives can be prepared and the properties of such derivatives can be assessed by any method known to those skilled in the art for these desired properties.

  In certain embodiments, “derivative” refers to a chemically modified compound that still maintains the desired action of the compound prior to chemical modification. Such derivatives may have addition, removal or substitution of one or more chemical moieties relative to the parent molecule. Non-limiting examples of the types of modifications that can be made to the compounds and structures disclosed throughout this document include lower alkanes such as methyl, ethyl, propyl, or hydroxymethyl or aminomethyl groups; carboxyl groups and carbonyl groups; Hydroxyl; including nitric acid, amino, amide and azo groups; addition or removal of substituted lower alkanes such as sulfuric acid, sulfonic acid, sulfone, sulfhydryl, sulfonyl, sulfoxide, phosphoric acid, phosphono, phosphoryl groups and halide substituents. Further modifications may include the addition or removal of one or more atoms of the atomic skeleton, such as, for example, substitution of ethyl with propyl, substitution of phenyl with larger or smaller aromatic groups. Alternatively, in a cyclic or bicyclic structure, a heteroatom such as N, S or O can be substituted for that structure instead of a carbon atom.

G. Equivalents Known and unknown equivalents to the components discussed throughout this specification can be used with the compositions and methods of the present invention. In some cases, for example, equivalents can be used as a substitute. In addition, equivalents can be used in addition to the methods and compositions of the invention. One skilled in the art will recognize and identify acceptable known or unknown equivalents to the components without undue experimentation.

H. Kit In a further embodiment of the invention, a kit is provided. In a non-limiting embodiment, the kit can include a pharmaceutical composition of the present invention, as well as other components as set forth in the claims and specification. Kit containers can be bottles, dispensers, packages, dividers, syringes, needles (eg, gauges such as 7, 8, 9, 10, 15, 20, 25, 30, 31, 32, 33) or other types of containers Can be included. The container may include an indication on its surface. For example, the display can be a word, phrase, abbreviation, figure or symbol.

  The container can dispense a predetermined amount of a component (eg, the composition of the present invention). The composition can be formulated as a spray, aerosol, or liquid or semi-solid. The container can have a spray, pump or squeeze mechanism. In certain embodiments, the kit can include a syringe for administering the composition of the invention.

  If there are multiple components in the kit (which are packaged together), the kit may also contain a second, third or other additional container, generally where the additional components are placed separately. The kit of the present invention may also include a container for storing the components in a tightly sealed state for commercial sale. Such containers may include injection or blow molded plastic containers holding the desired bottles, dispensers or packages.

  The kit can also include instructions for using the components of the kit and for any other composition, compound, agent, active ingredient or product not included in the kit. The instructions may include possible changes. The instructions can include, for example, instructions on how to apply, use and maintain the product or composition.

  All of the compositions and / or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of the present invention have been described with reference to preferred embodiments, modifications can be made to the compositions and / or methods and herein without departing from the concept, spirit and scope of the present invention. It will be apparent to those skilled in the art that the method steps or series of steps described can be applied. More specifically, it will be apparent that certain chemically and physically related agents can achieve the same or similar results while being interchangeable with the agents described herein. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.

References The following references are specifically incorporated by reference to the extent that these references provide experimental procedures or other details that supplement those set forth herein.

Claims (20)

  Water-insoluble polymer comprising a polyester polymer or a fatty acid-based polymer, or a mixture of both polymers, wherein the melting point of the polymer matrix is less than 60 ° C. and the composition is liquid or paste at room temperature and is formulated to plug the channel of interest A pharmaceutical composition comprising a matrix.   2. The pharmaceutical composition according to claim 1, wherein the composition comprises up to 50% (w / w) water miscible organic liquid.   A polymer matrix comprising poly (caprolactone), poly (ethylene glycol adipate), poly (propylene glycol adipate), poly (butylene glycol adipate), poly (hydroxybutarate), poly (hydroxyvalerate) and mixtures thereof and The pharmaceutical composition according to claim 1, comprising a polyester polymer selected from the group consisting of copolymers.   4. The pharmaceutical composition according to claim 3, wherein the polymer matrix comprises a poly (ε-caprolactone) polymer. The pharmaceutical composition according to claim 1, wherein the polymer matrix comprises a polyester polymer selected from the group consisting of:

Wherein R ₁ , R ₂ and R ₃ are independently selected from the group consisting of alkyl of 2 to 8 carbon atoms and alkoxyldiol, triol and tetraol;
w and w ₁ are independently integers of 4 to 12,
w ₂ and w ₃ are each independently an integer of 1 to 12,
w ₄ , w ₅ , w ₆ , w ₇ , w ₈ , w ₉ and w ₁₀ are independently integers from 0 to 12,
n is an integer from 4 to 9,
m is an integer from 2 to 8). R _1, R ₂ and R ₃ butanediol independently, hexanediol, neopentyl glycol, diethylene glycol, is selected from the group consisting of trimethylolpropane and pentaerythritol, pharmaceutical composition according to claim 5. The pharmaceutical composition according to claim 1, wherein the polymer matrix comprises a fatty acid polymer having a structure of the following formula:

In which A is an aliphatic hydroxycarboxylic acid ester of 6 to 60 carbon atoms;
B is a diacid dimer of an unsaturated fatty acid of 8 to 40 carbon atoms;
n is an integer from 0 to 3). 8. A pharmaceutical composition according to claim 7, wherein A has the structure:

(Wherein a, b, c, d, e and f are independently alkyl groups in the range of 1-15 or more linear carbons). The pharmaceutical composition according to claim 7, wherein B has a structure of the following formula:

(Wherein g, h, i and j are independently alkyl groups in the range of 1 to 15 or more linear carbons).   The pharmaceutical composition according to claim 1, wherein the polymer matrix comprises a polyester polymer having an average molecular weight of 400 to 8,000.   2. The pharmaceutical composition according to claim 1, wherein the composition has a viscosity of 50 to 8,000 cps at 55 [deg.] C.   2. A pharmaceutical composition according to claim 1 wherein the polymer matrix or composition is bioerodible.   The pharmaceutical composition according to claim 1, wherein the active agent is dispersed within the polymer matrix.   A method of occluding a tubule channel or punctum channel of a subject comprising administering the pharmaceutical composition of claim 1 to the channel.   15. The method of claim 14, wherein the pharmaceutical composition is not preheated prior to administering the composition to the channel.   15. The method of claim 14, wherein the pharmaceutical composition is injected into the channel with a needle.   A pharmaceutical composition of claim 1 is administered to a tubule or punctal channel of a subject, the composition comprising reducing tear drainage from the eye through the tubule channel or punctal opening of the subject How to treat dry eye syndrome.   18. The method of claim 17, wherein the pharmaceutical composition matches the shape of the tubule or punctal channel.   18. A method according to claim 17, wherein the pharmaceutical composition is formulated into an injectable paste or liquid.   A kit comprising the pharmaceutical composition of claim 1 and a syringe.

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